All Publications

Abstract

Math anxiety is a negative emotional reaction that is characterized by feelings of stress and anxiety in situations involving mathematical problem solving. High math-anxious individuals tend to avoid situations involving mathematics and are less likely to pursue science, technology, engineering, and math-related careers than those with low math anxiety. Math anxiety during childhood, in particular, has adverse long-term consequences for academic and professional success. Identifying cognitive interventions and brain mechanisms by which math anxiety can be ameliorated in children is therefore critical. Here we investigate whether an intensive 8 week one-to-one cognitive tutoring program designed to improve mathematical skills reduces childhood math anxiety, and we identify the neurobiological mechanisms by which math anxiety can be reduced in affected children. Forty-six children in grade 3, a critical early-onset period for math anxiety, participated in the cognitive tutoring program. High math-anxious children showed a significant reduction in math anxiety after tutoring. Remarkably, tutoring remediated aberrant functional responses and connectivity in emotion-related circuits anchored in the basolateral amygdala. Crucially, children with greater tutoring-induced decreases in amygdala reactivity had larger reductions in math anxiety. Our study demonstrates that sustained exposure to mathematical stimuli can reduce math anxiety and highlights the key role of the amygdala in this process. Our findings are consistent with models of exposure-based therapy for anxiety disorders and have the potential to inform the early treatment of a disability that, if left untreated in childhood, can lead to significant lifelong educational and socioeconomic consequences in affected individuals.Math anxiety during early childhood has adverse long-term consequences for academic and professional success. It is therefore important to identify ways to alleviate math anxiety in young children. Surprisingly, there have been no studies of cognitive interventions and the underlying neurobiological mechanisms by which math anxiety can be ameliorated in young children. Here, we demonstrate that intensive 8 week one-to-one cognitive tutoring not only reduces math anxiety but also remarkably remediates aberrant functional responses and connectivity in emotion-related circuits anchored in the amygdala. Our findings are likely to propel new ways of thinking about early treatment of a disability that has significant implications for improving each individual's academic and professional chances of success in today's technological society that increasingly demands strong quantitative skills.

Abstract

Competency with numbers is essential in today's society; yet, up to 20% of children exhibit moderate to severe mathematical learning disabilities (MLD). Behavioural intervention can be effective, but the neurobiological mechanisms underlying successful intervention are unknown. Here we demonstrate that eight weeks of 1:1 cognitive tutoring not only remediates poor performance in children with MLD, but also induces widespread changes in brain activity. Neuroplasticity manifests as normalization of aberrant functional responses in a distributed network of parietal, prefrontal and ventral temporal-occipital areas that support successful numerical problem solving, and is correlated with performance gains. Remarkably, machine learning algorithms show that brain activity patterns in children with MLD are significantly discriminable from neurotypical peers before, but not after, tutoring, suggesting that behavioural gains are not due to compensatory mechanisms. Our study identifies functional brain mechanisms underlying effective intervention in children with MLD and provides novel metrics for assessing response to intervention.

Abstract

Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show that there are more instances of greater functional connectivity in the brains of children with ASD in comparison to those of typically developing children. Hyperconnectivity in ASD was observed at the whole-brain and subsystems levels, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyperconnectivity predicted symptom severity in ASD, such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain of children with ASD is largely functionally hyperconnected in ways that contribute to social dysfunction. Our findings provide unique insights into brain mechanisms underlying childhood autism.

Neural predictors of individual differences in response to math tutoring in primary-grade school childrenPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICASupekar, K., Swigart, A. G., Tenison, C., Jolles, D. D., Rosenberg-Lee, M., Fuchs, L., Menon, V.2013; 110 (20): 8230-8235

Abstract

Now, more than ever, the ability to acquire mathematical skills efficiently is critical for academic and professional success, yet little is known about the behavioral and neural mechanisms that drive some children to acquire these skills faster than others. Here we investigate the behavioral and neural predictors of individual differences in arithmetic skill acquisition in response to 8-wk of one-to-one math tutoring. Twenty-four children in grade 3 (ages 8-9 y), a critical period for acquisition of basic mathematical skills, underwent structural and resting-state functional MRI scans pretutoring. A significant shift in arithmetic problem-solving strategies from counting to fact retrieval was observed with tutoring. Notably, the speed and accuracy of arithmetic problem solving increased with tutoring, with some children improving significantly more than others. Next, we examined whether pretutoring behavioral and brain measures could predict individual differences in arithmetic performance improvements with tutoring. No behavioral measures, including intelligence quotient, working memory, or mathematical abilities, predicted performance improvements. In contrast, pretutoring hippocampal volume predicted performance improvements. Furthermore, pretutoring intrinsic functional connectivity of the hippocampus with dorsolateral and ventrolateral prefrontal cortices and the basal ganglia also predicted performance improvements. Our findings provide evidence that individual differences in morphometry and connectivity of brain regions associated with learning and memory, and not regions typically involved in arithmetic processing, are strong predictors of responsiveness to math tutoring in children. More generally, our study suggests that quantitative measures of brain structure and intrinsic brain organization can provide a more sensitive marker of skill acquisition than behavioral measures.

Abstract

Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI) to investigate the maturation of control processes underlying problem solving skills in 7-9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI), ventrolateral prefrontal cortex and anterior cingulate cortex, and the fronto-parietal central executive network, anchored in dorsolateral prefrontal cortex and posterior parietal cortex (PPC). We found that, by age 9, the AI node of the salience network is a major causal hub initiating control signals during problem solving. Critically, despite stronger AI activation, the strength of causal regulatory influences from AI to the PPC node of the central executive network was significantly weaker and contributed to lower levels of behavioral performance in children compared to adults. These results were validated using two different analytic methods for estimating causal interactions in fMRI data. In parallel, DTI-based tractography revealed weaker AI-PPC structural connectivity in children. Our findings point to a crucial role of AI connectivity, and its causal cross-network influences, in the maturation of dynamic top-down control signals underlying cognitive development. Overall, our study demonstrates how a unified neurocognitive network model when combined with multimodal imaging enhances our ability to generalize beyond individual task-activated foci and provides a common framework for elucidating key features of brain and cognitive development. The quantitative approach developed is likely to be useful in investigating neurodevelopmental disorders, in which control processes are impaired, such as autism and ADHD.

Abstract

Functional and structural maturation of networks comprised of discrete regions is an important aspect of brain development. The default-mode network (DMN) is a prominent network which includes the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), medial temporal lobes (MTL), and angular gyrus (AG). Despite increasing interest in DMN function, little is known about its maturation from childhood to adulthood. Here we examine developmental changes in DMN connectivity using a multimodal imaging approach by combining resting-state fMRI, voxel-based morphometry and diffusion tensor imaging-based tractography. We found that the DMN undergoes significant developmental changes in functional and structural connectivity, but these changes are not uniform across all DMN nodes. Convergent structural and functional connectivity analyses suggest that PCC-mPFC connectivity along the cingulum bundle is the most immature link in the DMN of children. Both PCC and mPFC also showed gray matter volume differences, as well as prominent macrostructural and microstructural differences in the dorsal cingulum bundle linking these regions. Notably, structural connectivity between PCC and left MTL was either weak or non-existent in children, even though functional connectivity did not differ from that of adults. These results imply that functional connectivity in children can reach adult-like levels despite weak structural connectivity. We propose that maturation of PCC-mPFC structural connectivity plays an important role in the development of self-related and social-cognitive functions that emerge during adolescence. More generally, our study demonstrates how quantitative multimodal analysis of anatomy and connectivity allows us to better characterize the heterogeneous development and maturation of brain networks.

Abstract

The ontogeny of large-scale functional organization of the human brain is not well understood. Here we use network analysis of intrinsic functional connectivity to characterize the organization of brain networks in 23 children (ages 7-9 y) and 22 young-adults (ages 19-22 y). Comparison of network properties, including path-length, clustering-coefficient, hierarchy, and regional connectivity, revealed that although children and young-adults' brains have similar "small-world" organization at the global level, they differ significantly in hierarchical organization and interregional connectivity. We found that subcortical areas were more strongly connected with primary sensory, association, and paralimbic areas in children, whereas young-adults showed stronger cortico-cortical connectivity between paralimbic, limbic, and association areas. Further, combined analysis of functional connectivity with wiring distance measures derived from white-matter fiber tracking revealed that the development of large-scale brain networks is characterized by weakening of short-range functional connectivity and strengthening of long-range functional connectivity. Importantly, our findings show that the dynamic process of over-connectivity followed by pruning, which rewires connectivity at the neuronal level, also operates at the systems level, helping to reconfigure and rebalance subcortical and paralimbic connectivity in the developing brain. Our study demonstrates the usefulness of network analysis of brain connectivity to elucidate key principles underlying functional brain maturation, paving the way for novel studies of disrupted brain connectivity in neurodevelopmental disorders such as autism.

Abstract

Functional brain networks detected in task-free ("resting-state") functional magnetic resonance imaging (fMRI) have a small-world architecture that reflects a robust functional organization of the brain. Here, we examined whether this functional organization is disrupted in Alzheimer's disease (AD). Task-free fMRI data from 21 AD subjects and 18 age-matched controls were obtained. Wavelet analysis was applied to the fMRI data to compute frequency-dependent correlation matrices. Correlation matrices were thresholded to create 90-node undirected-graphs of functional brain networks. Small-world metrics (characteristic path length and clustering coefficient) were computed using graph analytical methods. In the low frequency interval 0.01 to 0.05 Hz, functional brain networks in controls showed small-world organization of brain activity, characterized by a high clustering coefficient and a low characteristic path length. In contrast, functional brain networks in AD showed loss of small-world properties, characterized by a significantly lower clustering coefficient (p<0.01), indicative of disrupted local connectivity. Clustering coefficients for the left and right hippocampus were significantly lower (p<0.01) in the AD group compared to the control group. Furthermore, the clustering coefficient distinguished AD participants from the controls with a sensitivity of 72% and specificity of 78%. Our study provides new evidence that there is disrupted organization of functional brain networks in AD. Small-world metrics can characterize the functional organization of the brain in AD, and our findings further suggest that these network measures may be useful as an imaging-based biomarker to distinguish AD from healthy aging.

Abstract

Causal estimation methods are increasingly being used to investigate functional brain networks in fMRI, but there are continuing concerns about the validity of these methods.Multivariate Dynamical Systems (MDS) is a state-space method for estimating dynamic causal interactions in fMRI data. Here we validate MDS using benchmark simulations as well as simulations from a more realistic stochastic neurophysiological model. Finally, we applied MDS to investigate dynamic casual interactions in a fronto-cingulate-parietal control network using Human Connectome Project (HCP) data acquired during performance of a working memory task. Crucially, since the ground truth in experimental data is unknown, we conducted novel stability analysis to determine robust causal interactions within this network.MDS accurately recovered dynamic causal interactions with an area under receiver operating characteristic (AUC) above 0.7 for benchmark datasets and AUC above 0.9 for datasets generated using the neurophysiological model. In experimental fMRI data, bootstrap procedures revealed a stable pattern of causal influences from the anterior insula to other nodes of the fronto-cingulate-parietal network.MDS is effective in estimating dynamic causal interactions in both the benchmark and neurophysiological model based datasets in terms of AUC, sensitivity and false positive rates.Our findings demonstrate that MDS can accurately estimate causal interactions in fMRI data. Neurophysiological models and stability analysis provide a general framework for validating computational methods designed to estimate causal interactions in fMRI. The right anterior insula functions as a causal hub during working memory.

Abstract

The medial temporal lobe (MTL), encompassing the hippocampus and parahippocampal gyrus (PHG), is a heterogeneous structure which plays a critical role in memory and cognition. Here, we investigate functional architecture of the human MTL along the long axis of the hippocampus and PHG. The hippocampus showed stronger connectivity with striatum, ventral tegmental area and amygdala-regions important for integrating reward and affective signals, whereas the PHG showed stronger connectivity with unimodal and polymodal association cortices. In the hippocampus, the anterior node showed stronger connectivity with the anterior medial temporal lobe and the posterior node showed stronger connectivity with widely distributed cortical and subcortical regions including those involved in sensory and reward processing. In the PHG, differences were characterized by a gradient of increasing anterior-to-posterior connectivity with core nodes of the default mode network. Left and right MTL connectivity patterns were remarkably similar, except for stronger left than right MTL connectivity with regions in the left MTL, the ventral striatum and default mode network. Graph theoretical analysis of MTL-based networks revealed higher node centrality of the posterior, compared to anterior and middle hippocampus. The PHG showed prominent gradients in both node degree and centrality along its anterior-to-posterior axis. Our findings highlight several novel aspects of functional heterogeneity in connectivity along the long axis of the human MTL and provide new insights into how its network organization supports integration and segregation of signals from distributed brain areas. The implications of our findings for a principledunderstanding of distributed pathways that support memory and cognition are discussed.

Abstract

Mathematical disabilities (MD) have a negative life-long impact on professional success, employment, and health outcomes. Yet little is known about the intrinsic functional brain organization that contributes to poor math skills in affected children. It is now increasingly recognized that math cognition requires coordinated interaction within a large-scale fronto-parietal network anchored in the intraparietal sulcus (IPS). Here we characterize intrinsic functional connectivity within this IPS-network in children with MD, relative to a group of typically developing (TD) children who were matched on age, gender, IQ, working memory, and reading abilities. Compared to TD children, children with MD showed hyper-connectivity of the IPS with a bilateral fronto-parietal network. Importantly, aberrant IPS connectivity patterns accurately discriminated children with MD and TD children, highlighting the possibility for using IPS connectivity as a brain-based biomarker of MD. To further investigate regional abnormalities contributing to network-level deficits in children with MD, we performed whole-brain analyses of intrinsic low-frequency fluctuations. Notably, children with MD showed higher low-frequency fluctuations in multiple fronto-parietal areas that overlapped with brain regions that exhibited hyper-connectivity with the IPS. Taken together, our findings suggest that MD in children is characterized by robust network-level aberrations, and is not an isolated dysfunction of the IPS. We hypothesize that intrinsic hyper-connectivity and enhanced low-frequency fluctuations may limit flexible resource allocation, and contribute to aberrant recruitment of task-related brain regions during numerical problem solving in children with MD.

Abstract

One of the most fundamental features of the human brain is its ability to detect and attend to salient goal-relevant events in a flexible manner. The salience network (SN), anchored in the anterior insula and the dorsal anterior cingulate cortex, plays a crucial role in this process through rapid detection of goal-relevant events and facilitation of access to appropriate cognitive resources. Here, we leverage the subsecond resolution of large multisession fMRI datasets from the Human Connectome Project and apply novel graph-theoretical techniques to investigate the dynamic spatiotemporal organization of the SN. We show that the large-scale brain dynamics of the SN are characterized by several distinctive and robust properties. First, the SN demonstrated the highest levels of flexibility in time-varying connectivity with other brain networks, including the frontoparietal network (FPN), the cingulate-opercular network (CON), and the ventral and dorsal attention networks (VAN and DAN). Second, dynamic functional interactions of the SN were among the most spatially varied in the brain. Third, SN nodes maintained a consistently high level of network centrality over time, indicating that this network is a hub for facilitating flexible cross-network interactions. Fourth, time-varying connectivity profiles of the SN were distinct from all other prefrontal control systems. Fifth, temporal flexibility of the SN uniquely predicted individual differences in cognitive flexibility. Importantly, each of these results was also observed in a second retest dataset, demonstrating the robustness of our findings. Our study provides fundamental new insights into the distinct dynamic functional architecture of the SN and demonstrates how this network is uniquely positioned to facilitate interactions with multiple functional systems and thereby support a wide range of cognitive processes in the human brain.

Abstract

State-space multivariate dynamical systems (MDS) (Ryali et al. 2011) and other causal estimation models are being increasingly used to identify directed functional interactions between brain regions. However, the validity and accuracy of such methods are poorly understood. Performance evaluation based on computer simulations of small artificial causal networks can address this problem to some extent, but they often involve simplifying assumptions that reduce biological validity of the resulting data. Here, we use a novel approach taking advantage of recently developed optogenetic fMRI (ofMRI) techniques to selectively stimulate brain regions while simultaneously recording high-resolution whole-brain fMRI data. ofMRI allows for a more direct investigation of causal influences from the stimulated site to brain regions activated downstream and is therefore ideal for evaluating causal estimation methods in vivo. We used ofMRI to investigate whether MDS models for fMRI can accurately estimate causal functional interactions between brain regions. Two cohorts of ofMRI data were acquired, one at Stanford University and the University of California Los Angeles (Cohort 1) and the other at the University of North Carolina Chapel Hill (Cohort 2). In each cohort, optical stimulation was delivered to the right primary motor cortex (M1). General linear model analysis revealed prominent downstream thalamic activation in Cohort 1, and caudate-putamen (CPu) activation in Cohort 2. MDS accurately estimated causal interactions from M1 to thalamus and from M1 to CPu in Cohort 1 and Cohort 2, respectively. As predicted, no causal influences were found in the reverse direction. Additional control analyses demonstrated the specificity of causal interactions between stimulated and target sites. Our findings suggest that MDS state-space models can accurately and reliably estimate causal interactions in ofMRI data and further validate their use for estimating causal interactions in fMRI. More generally, our study demonstrates that the combined use of optogenetics and fMRI provides a powerful new tool for evaluating computational methods designed to estimate causal interactions between distributed brain regions.

Abstract

Plasticity of white matter tracts is thought to be essential for cognitive development and academic skill acquisition in children. However, a dearth of high-quality diffusion tensor imaging (DTI) data measuring longitudinal changes with learning, as well as methodological difficulties in multi-time point tract identification have limited our ability to investigate plasticity of specific white matter tracts. Here, we examine learning-related changes of white matter tracts innervating inferior parietal, prefrontal and temporal regions following an intense 2-month math tutoring program. DTI data were acquired from 18 third grade children, both before and after tutoring. A novel fiber tracking algorithm based on a White Matter Query Language (WMQL) was used to identify three sections of the superior longitudinal fasciculus (SLF) linking frontal and parietal (SLF-FP), parietal and temporal (SLF-PT) and frontal and temporal (SLF-FT) cortices, from which we created child-specific probabilistic maps. The SLF-FP, SLF-FT, and SLF-PT tracts identified with the WMQL method were highly reliable across the two time points and showed close correspondence to tracts previously described in adults. Notably, individual differences in behavioral gains after 2 months of tutoring were specifically correlated with plasticity in the left SLF-FT tract. Our results extend previous findings of individual differences in white matter integrity, and provide important new insights into white matter plasticity related to math learning in childhood. More generally, our quantitative approach will be useful for future studies examining longitudinal changes in white matter integrity associated with cognitive skill development.

Abstract

Coordinated attention to information from multiple senses is fundamental to our ability to respond to salient environmental events, yet little is known about brain network mechanisms that guide integration of information from multiple senses. Here we investigate dynamic causal mechanisms underlying multisensory auditory-visual attention, focusing on a network of right-hemisphere frontal-cingulate-parietal regions implicated in a wide range of tasks involving attention and cognitive control. Participants performed three 'oddball' attention tasks involving auditory, visual and multisensory auditory-visual stimuli during fMRI scanning. We found that the right anterior insula (rAI) demonstrated the most significant causal influences on all other frontal-cingulate-parietal regions, serving as a major causal control hub during multisensory attention. Crucially, we then tested two competing models of the role of the rAI in multisensory attention: an 'integrated' signaling model in which the rAI generates a common multisensory control signal associated with simultaneous attention to auditory and visual oddball stimuli versus a 'segregated' signaling model in which the rAI generates two segregated and independent signals in each sensory modality. We found strong support for the integrated, rather than the segregated, signaling model. Furthermore, the strength of the integrated control signal from the rAI was most pronounced on the dorsal anterior cingulate and posterior parietal cortices, two key nodes of saliency and central executive networks respectively. These results were preserved with the addition of a superior temporal sulcus region involved in multisensory processing. Our study provides new insights into the dynamic causal mechanisms by which the AI facilitates multisensory attention.

Abstract

Male predominance is a prominent feature of autism spectrum disorders (ASD), with a reported male to female ratio of 4:1. Because of the overwhelming focus on males, little is known about the neuroanatomical basis of sex differences in ASD. Investigations of sex differences with adequate sample sizes are critical for improving our understanding of the biological mechanisms underlying ASD in females.We leveraged the open-access autism brain imaging data exchange (ABIDE) dataset to obtain structural brain imaging data from 53 females with ASD, who were matched with equivalent samples of males with ASD, and their typically developing (TD) male and female peers. Brain images were processed with FreeSurfer to assess three key features of local cortical morphometry: volume, thickness, and gyrification. A whole-brain approach was used to identify significant effects of sex, diagnosis, and sex-by-diagnosis interaction, using a stringent threshold of p

Abstract

Early childhood anxiety has been linked to an increased risk for developing mood and anxiety disorders. Little, however, is known about its effect on the brain during a period in early childhood when anxiety-related traits begin to be reliably identifiable. Even less is known about the neurodevelopmental origins of individual differences in childhood anxiety.We combined structural and functional magnetic resonance imaging with neuropsychological assessments of anxiety based on daily life experiences to investigate the effects of anxiety on the brain in 76 young children. We then used machine learning algorithms with balanced cross-validation to examine brain-based predictors of individual differences in childhood anxiety.Even in children as young as ages 7 to 9, high childhood anxiety is associated with enlarged amygdala volume and this enlargement is localized specifically to the basolateral amygdala. High childhood anxiety is also associated with increased connectivity between the amygdala and distributed brain systems involved in attention, emotion perception, and regulation, and these effects are most prominent in basolateral amygdala. Critically, machine learning algorithms revealed that levels of childhood anxiety could be reliably predicted by amygdala morphometry and intrinsic functional connectivity, with the left basolateral amygdala emerging as the strongest predictor.Individual differences in anxiety can be reliably detected with high predictive value in amygdala-centric emotion circuits at a surprisingly young age. Our study provides important new insights into the neurodevelopmental origins of anxiety and has significant implications for the development of predictive biomarkers to identify children at risk for anxiety disorders.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits. While such deficits have been the focus of most research, recent evidence suggests that individuals with ASD may exhibit cognitive strengths in domains such as mathematics.Cognitive assessments and functional brain imaging were used to investigate mathematical abilities in 18 children with ASD and 18 age-, gender-, and IQ-matched typically developing (TD) children. Multivariate classification and regression analyses were used to investigate whether brain activity patterns during numerical problem solving were significantly different between the groups and predictive of individual mathematical abilities.Children with ASD showed better numerical problem solving abilities and relied on sophisticated decomposition strategies for single-digit addition problems more frequently than TD peers. Although children with ASD engaged similar brain areas as TD children, they showed different multivariate activation patterns related to arithmetic problem complexity in ventral temporal-occipital cortex, posterior parietal cortex, and medial temporal lobe. Furthermore, multivariate activation patterns in ventral temporal-occipital cortical areas typically associated with face processing predicted individual numerical problem solving abilities in children with ASD but not in TD children.Our study suggests that superior mathematical information processing in children with ASD is characterized by a unique pattern of brain organization and that cortical regions typically involved in perceptual expertise may be utilized in novel ways in ASD. Our findings of enhanced cognitive and neural resources for mathematics have critical implications for educational, professional, and social outcomes for individuals with this lifelong disorder.

Abstract

Analyzing Functional Magnetic Resonance Imaging (fMRI) of resting brains to determine the spatial location and activity of intrinsic brain networks--a novel and burgeoning research field--is limited by the lack of ground truth and the tendency of analyses to overfit the data. Independent Component Analysis (ICA) is commonly used to separate the data into signal and Gaussian noise components, and then map these components on to spatial networks. Identifying noise from this data, however, is a tedious process that has proven hard to automate, particularly when data from different institutions, subjects, and scanners is used. Here we present an automated method to delineate noisy independent components in ICA using a data-driven infrastructure that queries a database of 246 spatial and temporal features to discover a computational signature of different types of noise. We evaluated the performance of our method to detect noisy components from healthy control fMRI (sensitivity = 0.91, specificity = 0.82, cross validation accuracy (CVA) = 0.87, area under the curve (AUC) = 0.93), and demonstrate its generalizability by showing equivalent performance on (1) an age- and scanner-matched cohort of schizophrenia patients from the same institution (sensitivity = 0.89, specificity = 0.83, CVA = 0.86), (2) an age-matched cohort on an equivalent scanner from a different institution (sensitivity = 0.88, specificity = 0.88, CVA = 0.88), and (3) an age-matched cohort on a different scanner from a different institution (sensitivity = 0.72, specificity = 0.92, CVA = 0.79). We additionally compare our approach with a recently published method. Our results suggest that our method is robust to noise variations due to population as well as scanner differences, thereby making it well suited to the goal of automatically distinguishing noise from functional networks to enable investigation of human brain function.

Abstract

IMPORTANCE Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. MAIN OUTCOMES AND MEASURES Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual's salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.

Abstract

BACKGROUND: The default mode network (DMN), a brain system anchored in the posteromedial cortex, has been identified as underconnected in adults with autism spectrum disorder (ASD). However, to date there have been no attempts to characterize this network and its involvement in mediating social deficits in children with ASD. Furthermore, the functionally heterogeneous profile of the posteromedial cortex raises questions regarding how altered connectivity manifests in specific functional modules within this brain region in children with ASD. METHODS: Resting-state functional magnetic resonance imaging and an anatomically informed approach were used to investigate the functional connectivity of the DMN in 20 children with ASD and 19 age-, gender-, and IQ-matched typically developing (TD) children. Multivariate regression analyses were used to test whether altered patterns of connectivity are predictive of social impairment severity. RESULTS: Compared with TD children, children with ASD demonstrated hyperconnectivity of the posterior cingulate and retrosplenial cortices with predominately medial and anterolateral temporal cortex. In contrast, the precuneus in ASD children demonstrated hypoconnectivity with visual cortex, basal ganglia, and locally within the posteromedial cortex. Aberrant posterior cingulate cortex hyperconnectivity was linked with severity of social impairments in ASD, whereas precuneus hypoconnectivity was unrelated to social deficits. Consistent with previous work in healthy adults, a functionally heterogeneous profile of connectivity within the posteromedial cortex in both TD and ASD children was observed. CONCLUSIONS: This work links hyperconnectivity of DMN-related circuits to the core social deficits in young children with ASD and highlights fundamental aspects of posteromedial cortex heterogeneity.

Underconnectivity between voice-selective cortex and reward circuitry in children with autismPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAAbrams, D. A., Lynch, C. J., Cheng, K. M., Phillips, J., Supekar, K., Ryali, S., Uddin, L. Q., Menon, V.2013; 110 (29): 12060-12065

Abstract

Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.

Abstract

Understanding the organization of the human brain requires identification of its functional subdivisions. Clustering schemes based on resting-state functional magnetic resonance imaging (fMRI) data are rapidly emerging as non-invasive alternatives to cytoarchitectonic mapping in postmortem brains. Here, we propose a novel spatio-temporal probabilistic parcellation scheme that overcomes major weaknesses of existing approaches by (i) modeling the fMRI time series of a voxel as a von Mises-Fisher distribution, which is widely used for clustering high dimensional data; (ii) modeling the latent cluster labels as a Markov random field, which provides spatial regularization on the cluster labels by penalizing neighboring voxels having different cluster labels; and (iii) introducing a prior on the number of labels, which helps in uncovering the number of clusters automatically from the data. Cluster labels and model parameters are estimated by an iterative expectation maximization procedure wherein, given the data and current estimates of model parameters, the latent cluster labels, are computed using α-expansion, a state of the art graph cut, method. In turn, given the current estimates of cluster labels, model parameters are estimated by maximizing the pseudo log-likelihood. The performance of the proposed method is validated using extensive computer simulations. Using novel stability analysis we examine the sensitivity of our methods to parameter initialization and demonstrate that the method is robust to a wide range of initial parameter values. We demonstrate the application of our methods by parcellating spatially contiguous as well as non-contiguous brain regions at both the individual participant and group levels. Notably, our analyses yield new data on the posterior boundaries of the supplementary motor area and provide new insights into functional organization of the insular cortex. Taken together, our findings suggest that our method is a powerful tool for investigating functional subdivisions in the human brain.

Abstract

While there is almost universal agreement amongst researchers that autism is associated with alterations in brain connectivity, the precise nature of these alterations continues to be debated. Theoretical and empirical work is beginning to reveal that autism is associated with a complex functional phenotype characterized by both hypo- and hyper-connectivity of large-scale brain systems. It is not yet understood why such conflicting patterns of brain connectivity are observed across different studies, and the factors contributing to these heterogeneous findings have not been identified. Developmental changes in functional connectivity have received inadequate attention to date. We propose that discrepancies between findings of autism related hypo-connectivity and hyper-connectivity might be reconciled by taking developmental changes into account. We review neuroimaging studies of autism, with an emphasis on functional magnetic resonance imaging studies of intrinsic functional connectivity in children, adolescents and adults. The consistent pattern emerging across several studies is that while intrinsic functional connectivity in adolescents and adults with autism is generally reduced compared with age-matched controls, functional connectivity in younger children with the disorder appears to be increased. We suggest that by placing recent empirical findings within a developmental framework, and explicitly characterizing age and pubertal stage in future work, it may be possible to resolve conflicting findings of hypo- and hyper-connectivity in the extant literature and arrive at a more comprehensive understanding of the neurobiology of autism.

Immature integration and segregation of emotion-related brain circuitry in young childrenPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAQin, S., Young, C. B., Supekar, K., Uddin, L. Q., Menon, V.2012; 109 (20): 7941-7946

Abstract

The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing children compared with twenty-four 19- to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry.

Abstract

Characterizing interactions between multiple brain regions is important for understanding brain function. Functional connectivity measures based on partial correlation provide an estimate of the linear conditional dependence between brain regions after removing the linear influence of other regions. Estimation of partial correlations is, however, difficult when the number of regions is large, as is now increasingly the case with a growing number of large-scale brain connectivity studies. To address this problem, we develop novel methods for estimating sparse partial correlations between multiple regions in fMRI data using elastic net penalty (SPC-EN), which combines L1- and L2-norm regularization We show that L1-norm regularization in SPC-EN provides sparse interpretable solutions while L2-norm regularization improves the sensitivity of the method when the number of possible connections between regions is larger than the number of time points, and when pair-wise correlations between brain regions are high. An issue with regularization-based methods is choosing the regularization parameters which in turn determine the selection of connections between brain regions. To address this problem, we deploy novel stability selection methods to infer significant connections between brain regions. We also compare the performance of SPC-EN with existing methods which use only L1-norm regularization (SPC-L1) on simulated and experimental datasets. Detailed simulations show that the performance of SPC-EN, measured in terms of sensitivity and accuracy is superior to SPC-L1, especially at higher rates of feature prevalence. Application of our methods to resting-state fMRI data obtained from 22 healthy adults shows that SPC-EN reveals a modular architecture characterized by strong inter-hemispheric links, distinct ventral and dorsal stream pathways, and a major hub in the posterior medial cortex - features that were missed by conventional methods. Taken together, our findings suggest that SPC-EN provides a powerful tool for characterizing connectivity involving a large number of correlated regions that span the entire brain.

Abstract

Analysis of dynamical interactions between distributed brain areas is of fundamental importance for understanding cognitive information processing. However, estimating dynamic causal interactions between brain regions using functional magnetic resonance imaging (fMRI) poses several unique challenges. For one, fMRI measures Blood Oxygenation Level Dependent (BOLD) signals, rather than the underlying latent neuronal activity. Second, regional variations in the hemodynamic response function (HRF) can significantly influence estimation of causal interactions between them. Third, causal interactions between brain regions can change with experimental context over time. To overcome these problems, we developed a novel state-space Multivariate Dynamical Systems (MDS) model to estimate intrinsic and experimentally-induced modulatory causal interactions between multiple brain regions. A probabilistic graphical framework is then used to estimate the parameters of MDS as applied to fMRI data. We show that MDS accurately takes into account regional variations in the HRF and estimates dynamic causal interactions at the level of latent signals. We develop and compare two estimation procedures using maximum likelihood estimation (MLE) and variational Bayesian (VB) approaches for inferring model parameters. Using extensive computer simulations, we demonstrate that, compared to Granger causal analysis (GCA), MDS exhibits superior performance for a wide range of signal to noise ratios (SNRs), sample length and network size. Our simulations also suggest that GCA fails to uncover causal interactions when there is a conflict between the direction of intrinsic and modulatory influences. Furthermore, we show that MDS estimation using VB methods is more robust and performs significantly better at low SNRs and shorter time series than MDS with MLE. Our study suggests that VB estimation of MDS provides a robust method for estimating and interpreting causal network interactions in fMRI data.

Abstract

The inferior parietal lobule (IPL) of the human brain is a heterogeneous region involved in visuospatial attention, memory, and mathematical cognition. Detailed description of connectivity profiles of subdivisions within the IPL is critical for accurate interpretation of functional neuroimaging studies involving this region. We separately examined functional and structural connectivity of the angular gyrus (AG) and the intraparietal sulcus (IPS) using probabilistic cytoarchitectonic maps. Regions-of-interest (ROIs) included anterior and posterior AG subregions (PGa, PGp) and 3 IPS subregions (hIP2, hIP1, and hIP3). Resting-state functional connectivity analyses showed that PGa was more strongly linked to basal ganglia, ventral premotor areas, and ventrolateral prefrontal cortex, while PGp was more strongly connected with ventromedial prefrontal cortex, posterior cingulate, and hippocampus-regions comprising the default mode network. The anterior-most IPS ROIs, hIP2 and hIP1, were linked with ventral premotor and middle frontal gyrus, while the posterior-most IPS ROI, hIP3, showed connectivity with extrastriate visual areas. In addition, hIP1 was connected with the insula. Tractography using diffusion tensor imaging revealed structural connectivity between most of these functionally connected regions. Our findings provide evidence for functional heterogeneity of cytoarchitectonically defined subdivisions within IPL and offer a novel framework for synthesis and interpretation of the task-related activations and deactivations involving the IPL during cognition.

Abstract

Multivariate pattern recognition methods are increasingly being used to identify multiregional brain activity patterns that collectively discriminate one cognitive condition or experimental group from another, using fMRI data. The performance of these methods is often limited because the number of regions considered in the analysis of fMRI data is large compared to the number of observations (trials or participants). Existing methods that aim to tackle this dimensionality problem are less than optimal because they either over-fit the data or are computationally intractable. Here, we describe a novel method based on logistic regression using a combination of L1 and L2 norm regularization that more accurately estimates discriminative brain regions across multiple conditions or groups. The L1 norm, computed using a fast estimation procedure, ensures a fast, sparse and generalizable solution; the L2 norm ensures that correlated brain regions are included in the resulting solution, a critical aspect of fMRI data analysis often overlooked by existing methods. We first evaluate the performance of our method on simulated data and then examine its effectiveness in discriminating between well-matched music and speech stimuli. We also compared our procedures with other methods which use either L1-norm regularization alone or support vector machine-based feature elimination. On simulated data, our methods performed significantly better than existing methods across a wide range of contrast-to-noise ratios and feature prevalence rates. On experimental fMRI data, our methods were more effective in selectively isolating a distributed fronto-temporal network that distinguished between brain regions known to be involved in speech and music processing. These findings suggest that our method is not only computationally efficient, but it also achieves the twin objectives of identifying relevant discriminative brain regions and accurately classifying fMRI data.

Abstract

Over the past several decades, structural MRI studies have provided remarkable insights into human brain development by revealing the trajectory of gray and white matter maturation from childhood to adolescence and adulthood. In parallel, functional MRI studies have demonstrated changes in brain activation patterns accompanying cognitive development. Despite these advances, studying the maturation of functional brain networks underlying brain development continues to present unique scientific and methodological challenges. Resting-state fMRI (rsfMRI) has emerged as a novel method for investigating the development of large-scale functional brain networks in infants and young children. We review existing rsfMRI developmental studies and discuss how this method has begun to make significant contributions to our understanding of maturing brain organization. In particular, rsfMRI has been used to complement studies in other modalities investigating the emergence of functional segregation and integration across short and long-range connections spanning the entire brain. We show that rsfMRI studies help to clarify and reveal important principles of functional brain development, including a shift from diffuse to focal activation patterns, and simultaneous pruning of local connectivity and strengthening of long-range connectivity with age. The insights gained from these studies also shed light on potentially disrupted functional networks underlying atypical cognitive development associated with neurodevelopmental disorders. We conclude by identifying critical gaps in the current literature, discussing methodological issues, and suggesting avenues for future research.

Abstract

Concept specific lexicons (e.g. diseases, drugs, anatomy) are a critical source of background knowledge for many medical language-processing systems. However, the rapid pace of biomedical research and the lack of constraints on usage ensure that such dictionaries are incomplete. Focusing on disease terminology, we have developed an automated, unsupervised, iterative pattern learning approach for constructing a comprehensive medical dictionary of disease terms from randomized clinical trial (RCT) abstracts, and we compared different ranking methods for automatically extracting con-textual patterns and concept terms. When used to identify disease concepts from 100 randomly chosen, manually annotated clinical abstracts, our disease dictionary shows significant performance improvement (F1 increased by 35-88%) over available, manually created disease terminologies.

Abstract

Reuse of ontologies is important for achieving better interoperability among health systems and relieving knowledge engineers from the burden of developing ontologies from scratch. Most of the work that aims to facilitate ontology reuse has focused on building ontology libraries that are simple repositories of ontologies or has led to keyword-based search tools that search among ontologies. To our knowledge, there are no operational methodologies that allow users to evaluate ontologies and to compare them in order to choose the most appropriate ontology for their task. In this paper, we present, Knowledge Zone - a Web-based portal that allows users to submit their ontologies, to associate metadata with their ontologies, to search for existing ontologies, to find ontology rankings based on user reviews, to post their own reviews, and to rate reviews.

Abstract

In order to make more informed healthcare decisions, consumers need information systems that deliver accurate and reliable information about their illnesses and potential treatments. Reports of randomized clinical trials (RCTs) provide reliable medical evidence about the efficacy of treatments. Current methods to access, search for, and retrieve RCTs are keyword-based, time-consuming, and suffer from poor precision. Personalized semantic search and medical evidence summarization aim to solve this problem. The performance of these approaches may improve if they have access to study subject descriptors (e.g. age, gender, and ethnicity), trial sizes, and diseases/symptoms studied. We have developed a novel method to automatically extract such subject demographic information from RCT abstracts. We used text classification augmented with a Hidden Markov Model to identify sentences containing subject demographics, and subsequently these sentences were parsed using Natural Language Processing techniques to extract relevant information. Our results show accuracy levels of 82.5%, 92.5%, and 92.0% for extraction of subject descriptors, trial sizes, and diseases/symptoms descriptors respectively.

Abstract

To build a common controlled vocabulary is a formidable challenge in medical informatics. Due to vast scale and multiplicity in interpretation of medical data, it is natural to face overlapping terminologies in the process of practicing medical informatics [A. Rector, Clinical terminology: why is it so hard? Methods Inf. Med. 38 (1999) 239-252]. A major concern lies in the integration of seemingly overlapping terminologies in the medical domain and this issue has not been well addressed. In this paper, we describe a novel approach for medical ontology integration that relies on the theory of Algorithmic Semantic Refinement we previously developed. Our approach simplifies the task of matching pairs of corresponding concepts derived from a pair of ontologies, which is vital to terminology mapping. A formal theory and algorithm for our approach have been devised and the application of this method to two medical terminologies has been developed. The result of our work is an integrated medical terminology and a methodology and implementation ready to use for other ontology integration tasks.

Abstract

The Stanford Tissue Microarray Database (TMAD) is a repository of data amassed by a consortium of pathologists and biomedical researchers. The TMAD data are annotated with multiple free-text fields, specifying the pathological diagnoses for each tissue sample. These annotations are spread out over multiple text fields and are not structured according to any ontology, making it difficult to integrate this resource with other biological and clinical data. We developed methods to map these annotations to the NCI thesaurus and the SNOMED-CT ontologies. Using these two ontologies we can effectively represent about 80% of the annotations in a structured manner. This mapping offers the ability to perform ontology driven querying of the TMAD data. We also found that 40% of annotations can be mapped to terms from both ontologies, providing the potential to align the two ontologies based on experimental data. Our approach provides the basis for a data-driven ontology alignment by mapping annotations of experimental data.

Abstract

Randomized clinical trials (RCT) papers provide reliable information about efficacy of medical interventions. Current keyword based search methods to retrieve medical evidence,overload users with irrelevant information as these methods often do not take in to consideration semantics encoded within abstracts and the search query. Personalized semantic search, intelligent clinical question answering and medical evidence summarization aim to solve this information overload problem. Most of these approaches will significantly benefit if the information available in the abstracts is structured into meaningful categories (e.g., background, objective, method, result and conclusion). While many journals use structured abstract format, majority of RCT abstracts still remain unstructured.We have developed a novel automated approach to structure RCT abstracts by combining text classification and Hidden Markov Modeling(HMM) techniques. Results (precision: 0.98, recall: 0.99) of our approach significantly outperform previously reported work on automated categorization of sentences in RCT abstracts.

Abstract

Medical Terminologies play a vital role in clinical data capture, reporting, information integration, indexing and retrieval. The Web Ontology language (OWL) provides an opportunity for the medical community to leverage the capabilities of OWL semantics and tools to build formal, sound and consistent medical terminologies, and to provide a standard web accessible medium for inter-operability,access and reuse. One of the tasks facing the medical community today is to represent the extensive terminology content that already exists into this new medium. This paper addresses one aspect of this challenge - how to incorporate multilingual, structured lexical information such as definitions, synonyms, usage notes, etc. into the OWL ontology model in a standardized, consistent and useful fashion.